Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant.

Published

Journal Article

Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers. We created four bivalent aptamers that can inhibit Factor X/Xa and prothrombin/thrombin and anticoagulate plasma, as well as the combination of individual aptamers. Detailed characterization of the shortest bivalent aptamer indicates that each aptamer retains full binding and functional activity when presented in the bivalent context. Finally, reversal of this bivalent aptamer with a single antidote was explored, and anticoagulant activity could be rapidly turned off in a dose-dependent manner. These studies demonstrate that bivalent anticoagulant aptamers represent a novel and potent approach to actively and reversibly control coagulation.

Full Text

Duke Authors

Cited Authors

  • Soule, EE; Bompiani, KM; Woodruff, RS; Sullenger, BA

Published Date

  • February 2016

Published In

Volume / Issue

  • 26 / 1

Start / End Page

  • 1 - 9

PubMed ID

  • 26584417

Pubmed Central ID

  • 26584417

Electronic International Standard Serial Number (EISSN)

  • 2159-3345

Digital Object Identifier (DOI)

  • 10.1089/nat.2015.0565

Language

  • eng

Conference Location

  • United States